Over 40 million American women are presently estrogen-deficient as a result of menopause. At age 50, an American woman can expect to live one-third of her life in menopause. Estrogen deficiency of menopause brings on changes that can have far reaching consequences on the future health and well-being of women. Alterations in cognitive functioning, particularly memory and attention, are experienced by postmenopausal women. Because estrogen modulates several brain regions that are important for cognitive function of postmenopausal women. However, the relationship between estrogen deficiency and cognitive changes experienced by postmenopausal women is highly controversial. Moreover, there is controversy whether estrogen replacement therapy (ERT) improves cognitive function in postmenopausal women, or women with Alzheimer's disease (AD) (who outnumber men with AD by 2:1). The relationship between estrogen states and cognitive function in menopause is difficult to study rigorously in women for a variety of reasons, including ethical considerations. An alternative is to examine these relationships in an appropriate animal model. Cynomolgus monkeys are a valuable model because they have menstrual cycles similar in pattern to women, they physiologically respond to estrogen deficiency and ERT in a manner similar to postmenopausal women, and they are capable of complex cognitive functions that parallel cognitive abilities in humans. In the present proposal, the effects of estrogen deficiency and ERT on cognitive abilities will be determined in surgically menopausal monkeys. Monkeys will be behaviorally characterized before and after ovariectomy, and during treatment with ERT, on a series of behavioral tasks that assess learning, memory and attention, cognitive abilities that are impaired in postmenopausal women. Moreover, the ability of chronic ERT to preserve cognitive function in surgically menopausal monkeys during pharmacologically challenges with cholinergic and dopaminergic amnestic agents also will be assessed. The broad objectives of this project are to provide a foundation of information about the relationship between cognition and estrogen states for a long-term research plan that will investigate interrelationships between hormonal states, cognition, aging, and neurobiology. Elucidating the relationship between estrogen states and cognitive function in monkeys will be valuable in guiding future clinical studies in postmenopausal women and women with AD, and in directing public health policy for treating postmenopausal women in their remaining 20-30 years of life.